Abstract

TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer.

ISI Document Delivery No.: CX9SE
Times Cited: 0
Cited Reference Count: 54
Gouge, Jerome Satia, Karishma Guthertz, Nicolas Widya, Marcella Thompson, Andrew James Cousin, Pascal Dergai, Oleksandr Hernandez, Nouria Vannini, Alessandro
University of Lausanne; Swiss National Science Foundation (SNSF) [31003A_132958]; Career Development Faculty Program of the ICR; Biotechnology and Biological Sciences Research Council (BBSRC) [BB/K014390/1]
We thank N. Cronin at The Institute of Cancer Research (ICR) for help with the crystallization setup and data collection. We thank the staff at beamlines ID29 and ID23eh1 of the European Synchrotron Radiation Facility (France) and at beamlines I24 and IO3 of Diamond Light Source (UK) for help with data collection. We thank the laboratories of Chris Lord and Pascal Meier for help with siRNA and FACS analysis, Tracy Berg for help with qRT-PCR, and Fredrik Wallberg of the ICR Flow Cytometry Facility and Sarah Hanrahan of the Proteomics Core Facility. We thank Richard Maraia and Aneeshkumar Arimbasseri for critical reading of an early version of the manuscript and Sonja Christoph for support throughout the project. P.C., O.D., and N.H. were supported by the University of Lausanne and by Swiss National Science Foundation (SNSF) grant 31003A_132958. A.V. acknowledges the support of the Career Development Faculty Program of the ICR. Part of this work was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) new-investigator award (BB/K014390/1) to A.V.
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1
Cell press
Cambridge
1097-4172